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Synthesis method of alclometasone dipropionate intermediate of 11-beta hydroxypregna

A technology of hydroxypregna and dimethylformamide, which is applied in the field of synthesis of alclomethasone dipropionate intermediate 11-beta hydroxypregna, which can solve the problems of long production cycle, unsuitability for industrialization, long synthesis route, etc. problems, to achieve the effects of industrialization of production, shortening of preparation time, and mild reaction conditions

Active Publication Date: 2018-05-22
CHONGQING HUABANGSHENGKAI PHARM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] U.S. Patent No. 5,426,198 uses zinc powder, mercaptoacetic acid, and chromium trichloride to react in a mixed solvent of N,N dimethylformamide and tetrahydrofuran. The reaction is carried out at room temperature and reflux respectively at room temperature. It takes 2.5 days to complete the reaction at room temperature and reflux The reaction takes 1.1 hours, the purity of this method is 80-95%, the reaction time is long, the energy consumption is high, and the production cost is high, so it is not suitable for industrial production
[0006] The method of introducing 11-α hydroxyl by microbial transformation and then converting 11-α hydroxyl into 11-β hydroxyl by chemical synthesis is the most commonly used method for introducing 11-β and hydroxyl in steroid synthesis at home and abroad. Immature, long synthetic route, long production cycle, high production cost, not suitable for industrialization

Method used

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  • Synthesis method of alclometasone dipropionate intermediate of 11-beta hydroxypregna
  • Synthesis method of alclometasone dipropionate intermediate of 11-beta hydroxypregna
  • Synthesis method of alclometasone dipropionate intermediate of 11-beta hydroxypregna

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] 1) Add 1.2kg of chromium trichloride and 21.5L of dimethylformamide into a dry and clean 50L reactor under the condition of vacuuming and nitrogen deoxidation, stir and dissolve, cool down to -5~5℃, add 1.2kg of zinc powder, Then add 1.4kg of mercaptoacetic acid dropwise, and slowly add 3.4kg of the compound of formula II dissolved in 17.2L of dimethylformamide dropwise at -10 to 0°C, and the mixed solution has been vacuumized and deoxidized by nitrogen;

[0049] 2) React at a constant temperature of -10 to 0°C for 0.5 to 1.0 hours, and monitor the disappearance of raw materials by TLC (thin layer chromatography, chloroform: acetone = 4:1);

[0050] 3) Pour the reaction solution into 164L of ice water at 0-5°C, stir for 10-20 minutes and then centrifuge, stir and dissolve the filter cake with 40.0L of tetrahydrofuran, add anhydrous sodium sulfate to dry for 1 hour, and filter;

[0051] 4) Concentrate the filtrate until the flow is cut off, add ethyl acetate to dissolve ...

Embodiment 2

[0055] 1) Add 161.5g of chromium trichloride and 3.0L of dimethylacetamide in a dry and clean 10L reaction kettle under the condition of vacuuming and nitrogen deoxidation, stir and dissolve, cool down to -5~5℃, add 157.5g of zinc powder, Add 161.5g of mercaptoacetic acid dropwise, and slowly add 600g of the compound of formula II dissolved in 2.4L of dimethylacetamide dropwise at -10 to 0°C, and the mixed solution has been evacuated and deoxidized by nitrogen;

[0056] 2) React at a constant temperature of -10 to 0°C for 0.5 to 1.0 hours, and monitor the disappearance of raw materials by TLC (thin layer chromatography, chloroform: acetone = 4:1);

[0057] 3) Pour the reaction solution into 24L of ice water at 0-5°C, stir for 10-20 minutes and then centrifuge, stir and dissolve the filter cake with 8.0L tetrahydrofuran, add anhydrous sodium sulfate to dry for 1 hour, and filter;

[0058]4) Concentrate the filtrate until the flow is cut off, add ethyl acetate to dissolve the re...

Embodiment 3

[0062] 1) Add 113.0g of chromium trichloride, 1.0L of dimethylformamide and 1.1L of acetone into a dry and clean 10L reaction kettle under the condition of vacuuming and nitrogen deoxidation, stir and dissolve, cool down to -5~5℃ and add zinc powder 110.2gg, then add 140.6g of thioglycolic acid dropwise, and slowly add 420g of the compound of formula II dissolved in 1.7L of dimethylacetamide at -10 to 0°C, and the mixed solution has been evacuated and deoxidized by nitrogen;

[0063] 2) React at a constant temperature of -10 to 0°C for 0.5 to 1.0 hours, and monitor the disappearance of raw materials by TLC (thin layer chromatography, chloroform: acetone = 4:1);

[0064] 3) Pour the reaction solution into 20L of ice water at 0-5°C, stir for 10-20 minutes and then centrifuge, stir and dissolve the filter cake with 7.0L of tetrahydrofuran, add anhydrous sodium sulfate to dry for 1 hour, and filter;

[0065] 4) Concentrate the filtrate until the flow is cut off, add ethyl acetate ...

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Abstract

The invention belongs to the field of a medicine preparation, and particularly relates to a synthesis method of an alclometasone dipropionate intermediate of 11-beta hydroxypregna. The 11-beta hydroxypregna is obtained by using a compound shown as a formula II as raw materials and performing free radical reaction under the effects of zinc powder, hexahydrate chromium trichloride and thioglycolic acid. The method provided by the invention has the advantages that the operation is simple; the yield is high; the method is suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of pharmaceutical preparations, in particular to a method for synthesizing alclomethasone dipropionate intermediate 11-β-hydroxypregna. Background technique [0002] Aclomethasone dipropionate is a low-to-medium-effect corticosteroid drug, and pharmacological experiments have shown that it has anti-inflammatory, anti-allergic, and anti-proliferative effects. Clinically, aclomethasone dipropionate has anti-inflammatory, antipruritic and vasoconstrictive effects. It is generally believed that corticosteroids play an anti-inflammatory role by inducing lipocertins, inhibiting phospholipase A2 from hydrolyzing membrane phospholipids to release arachidonic acid, thereby controlling the biosynthesis of inflammatory mediators such as prostaglandins and leukotrienes, and exerting anti-inflammatory effects. As a very key intermediate of aclomethasone dipropionate, its structural formula is: [0003] [0004] The methods fo...

Claims

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Application Information

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IPC IPC(8): C07J7/00
CPCC07J7/008
Inventor 朱强杨玉金
Owner CHONGQING HUABANGSHENGKAI PHARM
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